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Publication numberUS20040138125 A1
Publication typeApplication
Application numberUS 10/744,114
Publication date15 Jul 2004
Filing date23 Dec 2003
Priority date24 Sep 2001
Also published asUS6683066, US20030059476, US20040142905, US20040142906, WO2003026565A2, WO2003026565A3
Publication number10744114, 744114, US 2004/0138125 A1, US 2004/138125 A1, US 20040138125 A1, US 20040138125A1, US 2004138125 A1, US 2004138125A1, US-A1-20040138125, US-A1-2004138125, US2004/0138125A1, US2004/138125A1, US20040138125 A1, US20040138125A1, US2004138125 A1, US2004138125A1
InventorsYanming Wang
Original AssigneeYanming Wang
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Composition and method to prevent and treat brain and spinal cord injuries
US 20040138125 A1
Abstract
A composition and method for treating and preventing injury to central nervous system tissue are provided. The composition is comprised of agents that can increase colloidal osmotic pressure and osmolality. The method comprise of: a). Withdrawing cerebrospinal fluid from the subarachnoid spaces around the tissue to be treated or protected and b). Injecting the composition into subarachnoid spaces.
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Claims(26)
1. A neuroprotective composition for protecting the central nervous system of a mammal comprising Poly-amino Acid.
2. A neuroprotective composition for protecting the central nervous system of a mammal comprising essentially Poly-amino Acid.
3. A neuroprotective composition for protecting the central nervous system of a mammal comprising % 0.1-20% Poly-amino Aci
4. A neuroprotective composition for protecting the central nervous system of a mammal comprising Poly-Lysine.
5. A neuroprotective composition for protecting the central nervous system of a mammal comprising essentially Poly-Lysine.
6. A neuroprotective composition for protecting the central nervous system of a mammal comprising Poly-D-Lysine.
7. A neuroprotective composition for protecting the central nervous system of a mammal comprising Poly-L-Lysine.
8. A neuroprotective composition for protecting the central nervous system of a mammal comprising Poly-Lysine with molecular weight between 70,000-150,000.
9. A neuroprotective composition for protecting the central nervous system of a mammal comprising gelatin.
10. A neuroprotective composition for protecting the central nervous system of a mammal comprising essentially gelatin.
11. A neuroprotective composition for protecting the central nervous system of a mammal comprising collagen.
12. A neuroprotective composition for protecting the central nervous system of a mammal comprising essentially collagen.
13. A neuroprotective composition for protecting the central nervous system of a mammal comprising a combination of Poly-amino Acid and a crystal osmotic agent.
14. A neuroprotective composition for protecting the central nervous system of a mammal comprising a combination of gelatin and a crystal osmotic agent.
15. A neuroprotective composition for protecting the central nervous system of a mammal comprising a combination of collagen and a crystal osmotic agent.
16. A neuroprotective composition according to claim 13,14 and 15 wherein said crystal osmotic agent is mannitol.
17. A neuroprotective composition according to claim 13,14 and 15 wherein said crystal osmotic agent is glucose.
18. A solution that can generate a colloidal osmotic pressure between 1-40 mm Hg with said neuroprotective composition according to claim 1 to 17.
19. A solution that can generate a colloidal osmotic pressure between 140 mm Hg and osmolality between 289-459 mOsm/L with said neuroprotective composition according to claim 1 to 17.
20. A method for protecting Central Nervous System tissue in need of such protection in mammal, comprising the steps of:
a). Withdrawing a volume of cerebrospinal fluid from the subarachnoid space,
b). Injecting a said neuroprotective composition according to claim 1 to 17 which is dissolved by certain amount of said cerebrospinal fluid into said subarachnoid space.
21. A method for protecting Central Nervous System tissue in need of such protection in mammal, comprising the steps of:
a). Withdrawing a volume of cerebrospinal fluid from the subarachnoid space,
b). Injecting a said solution according to claim 18 and 19 into said subarachnoid space.
22. A method for protecting Central Nervous System tissue in need of such protection in mammal according to claim 20 and 21, comprising added step of administering a CSF production-suppressing agent.
23. A method for protecting Central Nervous System tissue in need of such protection in mammal according to claim 20 and 21, comprising added step of administering a water channel blocker, such as Mersalyl.
24. A method for protecting Central Nervous System tissue in need of such protection in mammal according to claim 20 and 21, comprising added step of administering an effective amount of agent selected from the group consisting of: calcium channel blockers, calcium chelators, potassium channel blockers, free radical scavengers, antioxidants, GABA agonists, GABA receptor antagonists, glutamate antagonists, NMDA antagonists, NMDA channel blockers, glycine site antagonists, polyamine site antagonists, adenosine receptor antagonists, growth factors, Glial cell line derived neurotrophic factor (GDNF), brain derived neurotrophic factor, insulin like growth factor, leukocyte adhesion inhibitors, nitric oxide inhibitors, opiod antagonists, Serotonin agonists, sodium channel blockers, potassium channel openers, anti-inflamatory agents, and protein kinase inhibitors to said mammal.
25. A method for treating stroke in a mammal requiring such treatment according to claim 20 and 21 comprising added step of Administering a thrombolytic agent to said mammal in an amount effective to restore blood flow to central nervous system tissue.
26. A method according to claim 25 wherein said thrombolytic agent is recombinant tissue plasminogen activator (rt-PA).
Description
    RELATED APPLICATIONS
  • [0001]
    This application is a continuation in part of application Ser. No. 09/962,009, filed Sep. 24, 2001, and a continuation in part of two continuation Application filed Nov. 7, 2003, the disclosure of which is incorporated by reference.
  • BACKGROUND OF THE INVENTION
  • [0002]
    1. Field of the Invention
  • [0003]
    This invention is related to prevention and treatment for brain and spinal cord injuries. In particular, the invention relates to osmotic agents and the methods of using osmotic agents to prevent and protect the brain and spinal cord injuries in patients.
  • [0004]
    2. Background Information
  • [0005]
    Central nervous system (CNS) consisting of the brain and spinal cord is very vulnerable to injuries, such as hypoxia-ischemia, trauma, poisoning etc. Cerebral edema is a common pathway to all CNS injuries. Clinical prevention and treatment for CNS injuries induced edema includes intravenous administration of osmotic agent, diuretic, removal of cerebrospinal fluid, coticosterroids etc, however, the efficacy is temporary and limited. Current search for a neuroprotective treatment based on other molecular mechanisms has yielded a disappointing result including oxygen free radical scavengers, calcium channel blockers and glutamate receptor antagonists to monoclonal antibodies that attempt to curtail inflammatory cascades occurring in cerebral injuries etc.
  • [0006]
    The existence of the cerebrospinal fluid (CSF) is a unique feature of the CNS. In an adult human, the CSF volume ranges from about 52 to 160 ml (mean 140 ml), occupying 10 percent of the intra-cranial and intra-spinal volume. The choroid plexuses are the main sites of CSF formation. The average rate of CSF formation is about 21 to 22 ml/hr, or approximately 500 ml/day. The CSF as a whole is renewed four or five times daily. The CSF formation is related to intracranial pressure. When the intracranial pressure is below about 70 mm H2O, CSF is not absorbed, and production increases. To date, there is no definite evidence suggesting that the CSF is actively involved in the metabolism of the cells of the brain and spinal cord. The known primary function of CSF appears to be a mechanical one; it serves as a kind of water jacket for the spinal cord and brain, protecting them from potentially injurious blows to the spinal column and skull and acute changes in venous pressure. Therefore, the brain and spinal cord are merged in the CSF. The CSF also serves as a buoyancy so that the brain and spinal cord virtually float in a CSF jacket with weight being greatly reduced.
  • [0007]
    Although some researchers regard the CSF as lymphatic fluid of the CNS, the CSF is quite different from lymphatic fluid. First of all, in the peripheral tissues and organs, interstitial fluid and lymphatic fluid are separated, lymphatic fluid contain higher concentration of protein. Second, the interstitial fluid and lymphatic fluid pressure at capillary level is believed to be very low or even negative. However, although the CSF occupies the subarachnoid space, it has free access to neurons and surrounding glia cells through the Vichow-robin space which is also known as the perivascular spaces. Smaller blood vessels, which centripetally penetrate into the brain proper, are accompanied by an extension of the subarachnoid space that forms the Virchow-Robin space and is filled with the CSF. Importantly, the CSF is mainly composed of water and electrolytes. Although, the osmolality of the CSF is about 289 mOsm/L (almost equal to the plasma), but the colloidal pressure (COP) is very low because of the extremely low protein concentration. In addition, the intracranial pressure (ICP) is normally ranged between 80-180 mm H2O.
  • [0008]
    It has been known that after cardiac arrest and global ischemia, the brain suffers a “no-reflow” phenomenon. In the 1960s, Ames produced global cerebral ischemia for 6 minutes in rabbits followed by carbon black ink infusion. Ames found that a large amount of the brain suffered from perfusion deficits. Similar to the “no-reflow” phenomenon, post-ischemic or post-traumatic “hypoperfusion” has also been documented after spinal cord and brain injuries.
  • [0009]
    We have proposed that these unique physiological and anatomic features of the CNS place the brain and spinal cord in a very delicate edema prone position and play an important role in the vulnerability of the brain and spinal cord.
  • [0010]
    Our hypothesis is: The CSF is readily available to provide endless source of water to bath the CNS tissue; when the brain or spinal cord is injured by an initiating insult such as ischemia or trauma, the CSF infiltrates brain or spinal cord tissue through the injured cell membrane (or water channels) and causes the rapid development of edema. While excessive water inside the cell body is toxic, swelling of the tissue makes the Virchow-Robin space smaller and may even cause it to collapse, thereby compressing the small blood vessels and resulting in a obstruction of the blood flow, such as a “hypoperfusion” or even “no-reflow” phenomenon, which prolongs the original ischemic duration, blocks collateral circulation and induces a feedback loop. These events result in irreversible cell death, tissue necrosis and liquefaction, finally neurological deficits and even brain death become clinical outcomes. Therefore dealing with cerebral edema is the key for preventing or treating CNS injuries.
  • [0011]
    The osmosis in a living creature is not fully understood. Crystal osmotic pressure can suck water from the edematous tissue. For example, in clinic, while crystal osmotic agents such as glucose, mannitol or glycerin administration have strong and quick effect. However, the main function of a colloidal osmotic agent such as albumin is for holding water. The colloidal osmotic agents can prevent the water from entering tissue. The efficacy of a colloidal osmotic agent should mainly depend on its water-holding capacity.
  • [0012]
    In the formation of edema, the hydrostatic pressure is always the key contributor. It counteracts COP and promotes edema according to Starling's equation. However, it has less influence on crystal osmotic pressure. Importantly, in addition to the low colloidal pressure of the CSF, the ICP which is the hydrostatic pressure of the CSF, is often elevated when brain and spinal cord are injured.
  • [0013]
    U.S. patent filed Sep. 24, 2001 from Yanming Wang discloses a composition and treatment method for brain and spinal cord injuries.
  • [0014]
    Two U.S. patents of continuation of Sep. 24, 2001 from Yanming Wang filed Nov. 7, 2003 discloses compositions and treatment methods for brain and spinal cord injuries.
  • [0015]
    U.S. Pat. No. 6,500,809 to Frazer Glenn discloses a hyperoncotic artificial cerebrospinal fluid and method of treating neural tissue edema. Although the inventor increase the colloidal osmotic pressure in an artificial CSF fluid, it will be difficult to reduce the ICP with the method invented. They did not increase the crystal osmotic pressure of the artificial CSF which is also very important and effective to treat cerebral edema. In addition, there are many disadvantages regarding to this artificial CSF regarding its use, store, safety, high cost for patient etc.
  • [0016]
    A series of patents, U.S. Pat. Nos. 4,981,691, 4,758,431, 4,445,887, 4,445,500, and 4,393,863 to Osterholm disclose a fluorocarbon solution for treatment of hypoxic-ischemic neurological tissue.
  • SUMMARY OF THE INVENTION
  • [0017]
    Cerebral edema is a common pathway to all CNS injuries. All current clinical measures for prevention and treatment of CNS injuries induced edema only provide temporary and limited effect. Current search for a neuroprotective agent based on other molecular mechanisms has yielded a disappointing result.
  • [0018]
    Our hypothesis is: the two factors, i.e. the CSF and ICP, are the main reasons to cause the vulnerability of the CNS to injuries. The CSF, the very low colloidal osmotic pressure water solution, is readily available to provide endless source of water to bath the CNS tissue to cause the rapid development of edema when the brain or spinal cord is injured. The ICP promotes cerebral edema While excessive water inside the cell body is toxic, swelling of the tissue makes the Virchow-Robin space smaller, thereby compressing the small blood vessels and resulting in blood perfusion deficit, such as “hypoperfusion” or even “no-reflow” phenomenon, which prolongs the original ischemic duration, blocks collateral circulation and induces a feedback loop. These cascade events result in irreversible cell death, tissue necrosis and liquefaction, finally neurological deficits and even brain death become clinical outcomes. Therefore removing the CSF and increasing the osmotic pressure of the remaining CSF will reduce the cerebral edema herein increasing the cerebral flow and protecting the brain and spinal cord tissue.
  • [0019]
    This invention provides compositions and method for protecting brain and spinal cord. Compositions according to this invention may be used to treat neurological disorders, such as stroke, hypoxia-ischemia, hemorrhage, trauma, multiple sclerosis, seizure, infection, or poisoning. The compositions are also useful during open-heart surgery, aortic surgery, neurosurgery, shock, or other procedures where blood flow to the CNS is interrupted.
  • [0020]
    I have found the formulations I have used are effective when it is dissolved in patient's own CSF or simply dissolved in 5% Glucose or saline and applied to the subarachnoid spaces after the cerebrospinal fluid has been removed completely or partially from the subarachnoid spaces. These methods are effective to treat injured CNS tissue or to protect it from continuing damage after injury. To treat or prevent the CNS injuries, the composition will be dissolved in certain amount of the patient's own CSF or simply dissolved in 5% Glucose or saline and injected into subarachnoid spaces increasing the osmotic pressure around the injured CNS tissue to adsorb water from the edematous tissue and prevent water from further entering injurious tissue. Elimination of this cerebral edema prevents the onset of the “no-reflow” phenomenon or “hypoperfusion”, and protects the CNS tissue making it resistant to injuries, and lengthening the therapeutic window for all other therapies.
  • [0021]
    There are many advantages to the compositions and method I have discovered.
  • [0022]
    1. the composition and method provides an effective and simple approach to prevent and protect brain and spinal cord injuries.
  • [0023]
    2. it improves the efficacy of existing treatments for stroke, head trauma, and other invasive procedures. Administering an effective composition through subarachnoid spaces after removing the CSF according to this invention will increase the therapeutic window, the period of time in which any other treatment, including thrombolytic agents can be used. For example, tPA, the only FDA approved medication for stroke, is a thrombolytic agent targeted on dissolving the blood clots that led to the stroke. tPA is now only approved for use within 3 hours after onset of ischemia. When used in combination with the instant composition and method, the therapeutic window for all known treatments now used for supporting CNS tissue will be much longer. Another example is this invention if used before, during and after brain and spinal cord surgery, a quicker and better recovery result can be achieved.
  • [0024]
    3. the composition is easy to make and is convenient to store and transport to anywhere. For example, it can be easily stored at room temperature for long time; the volume is small and can be easily transported to anywhere; Using patient's own CSF or simply using 5% Glucose or saline to dissolve the composition is simple and provides more chance for clinical physician to adjust the dosage according to patient condition.
  • [0025]
    4. this invention also can reduce the cost of the treatment. Since the CSF is completely or partially removed, major water supply to cause the cerebral edema is eliminated. Therefore, the dosage is greatly reduced and efficacy is greatly enhanced. In addition, this invention provides more choices to make the composition, many of them are less expensive if large scale production is performed.
  • [0026]
    5. This invention, if combined with other known techniques such as controlled hypothermia, may significantly increase the length of time a patient can tolerate cerebral ischemia A patient treated according to this invention may survive invasive procedures performed on any part of the CNS without casing much injury, including areas of the brain that have not been surgically accessible prior to this invention such as brain stem. Additionally, procedures that require interruption of the blood flow, such as heart surgery, repair of aortic aneurysm, or any other surgery where systemic blood circulation is interrupted can be performed with increased safety.
  • [0027]
    6. The compositions and methods I have invented extend the therapeutic window for successfully resuscitating cardiac arrest from mere minutes to hours. In addition, this compositions and method are useful for screening neuroprotective agents developed based on other mechanisms.
  • DETAILED DESCRIPTION OF AN ILLUSTRATIVE EMBODIMENT
  • [0028]
    As we have discussed in the background information, two factors make the CNS vulnerable to injuries, i.e. the CSF itself is a low colloidal osmotic pressure water solution, the ICP, the hydrostatic pressure of the CSF can deduct the force of colloidal osmotic pressure to promote edema The CSF is readily available to provide endless source of water to bath the CNS tissue; when the brain or spinal cord is injured by an initiating insult such as ischemia or trauma, the CSF infiltrates brain or spinal cord tissue through the injured cell membrane (or water channels) and causes the rapid development of edema While excessive water inside the cell body is toxic, swelling of the tissue makes the Virchow-Robin space smaller and may even cause it to collapse, thereby compressing the small blood vessels and resulting in a obstruction of the blood flow, such as a “hypoperfusion” or even “no-reflow” phenomenon, which prolongs the original ischemic duration, blocks collateral circulation and induces a feedback loop. This failure of circulation results in continuing damage to CNS tissue after the interruption of blood flow is reversed leading to irreversible damage and eventually cell death, tissue necrosis and liquefaction, finally neurological deficits and even brain death become clinical outcomes.
  • [0029]
    Therefore dehydrating the edematous cerebral tissue is the most important issue to prevent and treat the brain and spinal cord injuries. As we all know, intravenously infusion of osmotic agents only provide temporary and limited effect, the reasonable strategy should target the CSF and ICP, i.e. decreasing the ICP and increasing the osmotic pressure of the CSF.
  • [0030]
    U.S. Pat. No. 6,500,809 to Frazer Glenn discloses a hyperoncotic artificial cerebrospinal fluid and method of treating neural tissue edema Although the inventor increase the COP in an artificial CSF fluid, it will be difficult to reduce the ICP with the method invented. They did not increase the crystal osmotic pressure of the artificial CSF which is also very important, particularly when the treatment is delayed and quick treatment is needed. There are many disadvantages for this artificial CSF. First of all, putting albumin in an artificial CSF is not more advantageous than just dissolving the albumin in patient's own CSF. Although albumin is good for maintain colloidal osmotic pressure, it is expensive and may be risky for being infected by HIV, Hepatitis virus B etc if the albumin is from human. In addition, it is not convenient to store and transfer this hyperoncotic artificial cerebrospinal fluid because it requires large volume of it to circulate in the cranium; Manufacturing a hyperoncotic artificial cerebrospinal fluid and circulating it are complicated and will have to add additional cost to a patient without enhancing drug effects. Although as the inventor stated in claim 31, the hyperoncotic artificial cerebrospinal fluid can be ultrafiltered and recirculated, the procedure is complicated and it seems wasting albumin is inevitable. According to the claim 21, this hyperoncotic artificial cerebrospinal fluid has to be circulated at the rate of 1-100 ml/min, this may result in elevated ICP leading to deduct osmotic pressure generated by albumin based on Starling's equation.
  • [0031]
    I have invented a composition comprising osmotic agents and a method to prevent and treat brain and spinal cord injuries.
  • [0032]
    To treat or prevent the brain and spinal cord injuries, first, removing the CSF to reduce the ICP and cut off the major water supply to cerebral tissue, then using part of the removed CSF as a solvent to dissolve the invented composition, second, injecting the composition which is dissolved by patient's own CSF to the affected area of the CNS tissue. Since the CSF injected back is relatively small portion of the whole CSF removed, the ICP will not be increased.
  • [0033]
    For maximum CNS tissue protection, two small holes are drilled on the skull, the dura is punctured, and a cannula is placed in through the dura into the subarachnoid spaces on the surface of the brain. Additional cannulas may be inserted into the lateral cerebral ventricles, the lumbar theca, and the cisterna magna. The CSF can be removed from any or all of these locations to remove edematous fluid. Optionally, for the treatment or prevention of localize injuries such as spinal cord injury, stroke, one cannula or two cannulas may be placed through a puncture in the lumbar theca or cisterna magna or the to the direct affected area.
  • [0034]
    In the instant method, the CSF (usually 5-200 ml) is withdrawn from the cranium and lumbar theca depending on the location of the injuries. If whole CNS needs to be protected such as cardiac arrest or during the cardiac surgery, the CSF should be removed as completely as possible. But for a localized injury such as stroke, head trauma, or for prevention of a localized injury during neurosurgery or aortic surgery, beneficial effects can be achieved upon removal of a lesser volume of the CSF. Although mechanically withdrawing CSF alone is not sufficient enough to achieve the neuroprotective effect, it reduces the ICP and cut off the major water supply to the cerebral tissue. By removing the CSF, the ICP can be reduced even to 0 mm H2O if necessary. Meanwhile, the CSF removed is saved for dissolving the composition described below and for injecting back. It is very difficult to completely remove all the CSF, the residual aqueous CSF after manual withdrawal can still cause edema and resultant “hypoperfusion” or “no-reflow” phenomenon, significantly decreasing the protective effect because it is a continued source of edematous fluid that can cause delayed or recurring injury. Therefore, our composition is needed.
  • [0035]
    The composition consists of both crystal and colloidal osmotic agents, it can be dry power form or liquid form. Although, many crystal osmotic agents can be chosen, such as glucose, mannitol, sorbitol, glycerin, sodium chloride, saccharose, saccharides, those used in clinic are preferred. Colloidal osmotic agents can be chosen from synthetic poly-amino acid, gelatin and collagen. Many poly-amino acids are commercially available, such as Poly-alanine, Poly-arginine, Poly-asparagine, Poly-cysteine, Poly-glutamate, Poly-histidine, Poly-isoleucine, Poly-ornithine, Poly-proline, Poly-Serine, Poly-tyrosine. Synthetic poly-lysine has high water-holding capacity. For example, because of rich in lysine, animal proteins are considered high quality protein having higher water-holding capacity. Therefore Synthetic poly-lysine with larger molecular weight should have even higher water-holding capacity than any natural proteins. For a synthetic product, it is easier for quality control with no risk of deadly virus contamination. Poly-D-Lysine, poly-L-Lysine and Poly-ornithine with molecular weight between 70,000-150,000 have been frequently used to coat plate for culturing neurons. Therefore these agents have been proven to be safe to neurons and are preferred to serve as colloidal osmotic agents in our composition. Poly-D-Lysine hydrobromide from Sigma-Aldrich are found effective. Gelatin and collagen all have better water-holding capacity. Gelatin that has been used as a colloidal plasma volume substitute clinically is found effective. GELOFUSINE« (containing 4-14% gelatin) from Mill-pledge Ltd may also be injected directly to the subarachnoid spaces or may add some crystal osmotic agents or diluted with small amount of the patent's own CSF before injection.
  • [0036]
    To make the composition, crystal osmotic agent and colloidal osmotic agent are mixed together. The crystal osmotic agent: colloidal osmotic agent should be 0.01-50 g: 100 g. Optionally, the crystal osmotic agent and the colloidal osmotic agent may be kept in two separated containers and let the physician decide their proportion according to the patient's condition. It is preferred that the crystal osmotic agent can create osmolality of about 20-140 mOsm/L. The pressure generated by colloidal osmotic agent is no limit but depending on the viscosity after being dissolved in the CSF. However, it is preferred that colloidal osmotic agent can create a pressure of 28-40 mm Hg. The composition can be manufactured and contained in different quantities in small mapules that is ready for being dissolved in 5 ml, 10 ml, 20 ml, 50 ml, 100 ml of the CSF. Patient's CSF, 5% glucose and 0.9% sodium chloride have normal osmolality (280-310 mOsm/L), therefore can all be used to dissolve the composition. The dissolved composition will have higher osmolality required. Optionally, the composition may be manufactured in a ready to use condition with crystal osmotic agent and colloidal osmotic agent mixed in 5% glucose, or 0.9% sodium chloride or artificial cerebrospinal fluid with final osmolality of 330-459 mOsm/L and COP of 2840 mm Hg.
  • [0037]
    To use the composition to prevent or to treat brain or spinal cord injuries, dissolving the composition in patient's own CSF, the clinical physician can decide the amount of the CSF being removed and dosage of the composition. Usually 5-160 ml of the patient's own CSF can be obtained as a solvent to dissolve the composition. For example, if a localized injury such as a spinal cord trauma, 5-20 ml of the patient's own CSF may be used. The CSF can be centrifuged and the supernatant can be used in case of blood in the CSF. Alternatively, simply using 5% glucose or 0.9% sodium chloride. The osmolality of the CSF after being dissolved with composition should be about, but not limited to, 330-459 mOsm/L, it is preferred that colloidal osmotic agents can create a pressure of 2840 mm Hg. After shaking well, the CSF with composition is injected back to the subarachnoid space through one or more cannulas. The CSF loaded with high osmotic agents stay around the injured brain or spinal cord tissue for certain period. While the crystal osmotic agent suck the water from edematous tissue, the colloidal osmotic agent hold the water from entering the tissue again. If necessary, the treatment procedure can be repeated. After patient is recovered, the composition can be removed by withdrawing the CSF again from the subarachnoid space.
  • [0038]
    Meanwhile, administering agent to suppress production of CSF can be advantageous. There are many known agents that inhibit production of CSF. All diuretics, include Furosemide (20-200 mg every 4-6 hours), and acetazolamide (0.25-2 g every 4-12 hours). Other agents known to suppress formation of CSF include: beta blocking agents such as isopranolol, and timolol maleate; and calcium channel blockers such as brinzolamide, dorzolamide, methazolamide, sezolamide, lantano-prost, and bis (carbonyl) amidothiadiazole sulfonamides; and carbonic acid anhydrase inhibitors such as triamterene, spironolactone, thiazides, and, Na and K-ATPase inhibitors. This CSF inhibiting agent can be administered intravenously, orally or by directly add to the invented composition injecting into subarachnoid space.
  • [0039]
    The recent discovery of water channels in the CNS provides a better explanation for the mechanism of brain edema Aquapprin-1 (AQP1), Aquapprin-4 (AQP4), Aquapprin-5 (AQP5), Aquapprin-9 (AQP9) water channels have been identified in CNS, and believed to play an important role in the development of cerebral edema The subarachnoid space is just like a reservoir containing the CSF water providing endless water supply for the CNS tissue. When injury occurs, CSF readily available to penetrate CNS tissues through water channels, while intracellular water unbalance exert direct toxicity to cells, swelling of the tissue around the Virchow-Robin space results in “hypoperfusion” or even “no-reflow” phenomenon, which prolongs the original ischemic duration, blocks collateral circulation and induces a feedback loop. Therefore the compositions and methods herein can be advantageously combined with water channel blocker. For example, Mercury has been identified as a water channel blocker, therefore Mersalyl, the potent diuretic may be effective.
  • [0040]
    The compositions and methods herein can be advantageously combined with any of the agents used to treat stroke or other neurological deficiencies including: calcium channel blockers such as Nimodipine, and Flunarizine; calcium chelators, such as DP-b99; potassium channel blockers; Free radical scavengers—Antioxidants such as Ebselen, porphyrin catalytic antioxidant manganese (III) meso-tetrakis (N-ethylpyridinium-2-yl) porphyrin, (MnTE-2-PyP (5+)), disodium 4-[(tert-butylimino) methyl] benzene-1,3-disulfonate N-oxide (NXY-059), N:-t-butyl-phenylnitrone or Tirilazad; GABA agonists including Clomethiazole; GABA receptor antagonists, glutamate antagonists, including AMPA antagonists such as GYKI 52466, NBQX, YM90K, YN872, ZK-200775 MPQX, Kainate antagonist SYM 2081, NMDA antagonists, including competitive NMDA antagonists such as CGS 19755 (Selfotel); NMDA channel blockers including Aptiganel (Cerestat), CP-101,606, Dextrorphan, destromethorphan, magnesium, metamine, MK-801, NPS 1506, and Remacemide; Glycine site antagonists including ACEA 1021, and GV 150026; polyamine site antagonists such as Eliprodil, and Ifenprodil; and adenosine receptor antagonists; Growth factors such as Fibroblast Growth Factor (bFGF), Glial cell line derived neurotrophic factor (GDNF), brain derived neurotrophic factor, insulin like growth factor, or neurotrophin; Leukocyte adhesion inhibitors such as Anti ICAM antibody (Enlimomab) and Hu23F2G; Nitric oxide inhibitors including Lubeluzole; opiod antagonists, such as Naloxone, Nalmefenem, Phosphatidylcholine precursor, Citicoline (CDP-coline); Serotonin agonists including Bay x 3072; Sodium channel blockers such as Fosphenytoin, Lubeluzole, and 619C89; Potassium channel openers such as BMS-204352; anti-inflamatory agents; protein kinase inhibitors, and other agents whose mechanism of action is unknown or uncertain including: Piracetam and albumin. Other active agents, that provide energy to cells, such as ATP, co-enzyme A, co-enzyme Q, or cytochrome C may be added. Similarly, agents known to reduce cellular demand for energy, such as phenytoin, barbital, or lithium may be added to the composition.
  • [0041]
    The compositions and methods can be combined with and enhance the efficiency of thrombolytic agents such as: recombinant tissue plasminogen activator (rtpA), streptokinase, and tenecteplase in dissolving thrombosis in management of stroke or myocardial infarction.
  • EXAMPLE ONE
  • [0042]
    Treatment of Spinal Cord Ischemia With our Method and Compositions
  • [0043]
    The acute spinal cord ischemia was induced in twenty-eight rabbits. Group one: control (4 rabbits). Group two: incomplete removal of the CSF (6 rabbits). Group three: treatment with composition I (6 rabbits).
  • [0044]
    Isoflorane was given for anesthesia A PE-90 tubing was surgically implanted in the cisterna magna, a PE-10 tubing was also implanted to the lumbar thecal sac in each rabbit. An abdominal incision was made and the aorta was isolated at the level of the renal artery. The aorta was cross-clamped by a clip just caudal to the left (lower) renal artery for one hour to produce spinal cord ischemic injury, then the clip was removed to resume blood supply.
  • [0045]
    For group one control, the CSF was not removed.
  • [0046]
    For group two, at 15 minutes after ischemia, the CSF was removed as completely as possible (usually 0.8-1.2 ml CSF could be withdrawn), then 0.1 ml CSF was immediately returned. To further ensure that the 0.1 ml of CSF returned to reach the lumber spinal cord uniformly, the rabbits on the plane operating board were kept in a slightly tilted position with head up (10 degrees), The ICP was maintained at 0-10 cm H2O.
  • [0047]
    For group three, at 15 minutes after ischemia, the CSF was removed as completely as possible (usually 0.8-1.2 ml CSF could be withdrawn). After the CSF removal, 0.5 ml of the CSF was used to dissolve composition I {40 mg Poly-D-lysine hydrobromide (molecular weight between 70,000-150,000) and 12.5 mg mannitol}, then was injected back through the PE-10 tubing. The ICP was maintained at 0-70 cm H2O during the ischemia.
  • [0048]
    At one week after ischemic injury, the rabbits were tested for behavioral deficit (grade 0: complete recovery; grade 1: able to stand, but unable to walk normally; grade 2: good movement of the hind limbs, but unable to stand; grade 3: spastic paraplegia with slight movement of the hind limbs; grade 4: spastic paraplegia with no movement to the hind limbs).
  • [0049]
    The result is summarized as following: At one week after ischemia, in group one and group two, all rabbits showed spastic paraplegia with no movement to the hind limbs (grade 4); In group three, no apparent deficit could be observed, all of rabbits walked and moved smoothly (grade 0).
  • EXAMPLE TWO
  • [0050]
    Treatment for Brain Ischemia With our Method and Compositions
  • [0051]
    The global cerebral ischemia was induced in twenty-two rabbits. Group one: control (4 rabbits). Group two: treatment with composition I (6 rabbits). Group three: treatment with composition II (6 rabbits).
  • [0052]
    Isoflorane was given for anesthesia. The trachea was incubated and connected to mechanical intermittent positive-pressure ventilation (tidal volume 30 ml, rate 50/min, O2 concentration 30%). A cannula was surgically positioned in the cisterna magna in each rabbit. A hole of 3 mm in diameter (4 mm lateral to midline and 3 mm posterior to the bregma) was drilled on each side of the skull, a cannula were positioned in the hole on each side through puncture. An arterial line was cannulated through femoral artery for monitoring blood pressure. A femoral vein was also cannulated for withdrawing and infusing blood. Four blood vessels (two common carotid arteries and two vertebrate arteries) were isolated and occluded for one hour with arterial clips to produce brain ischemia In order to produce complete global ischemia, 60-120 ml of blood was withdrawn to lower the blood pressure simultaneously. The mean blood pressure was maintained between 30-40 mmHg.
  • [0053]
    In group one, at 10 minutes after the global ischemia, 0.8-1.2 ml of CSF was withdrawn from caunnulas in cisterna magna and holes of the skull, then 0.30.6 ml of CSF was returned through the these caunnulas. The intracranial pressure was maintained at 0-70 cm H2O In group two, at 10 minutes after the global ischemia, 0.8-1.2 ml of CSF was withdrawn from caunnulas in cisterna magna and holes of the skull. After the CSF removal, 0.8 ml of the CSF was used to dissolve our composition I {64 mg Poly-D-lysine hydrobromide (molecular weight between 70,000-150,000) and 20 mg mannitol}, then was injected back through the caunnulas. The ICP was maintained at 0-70 cm H20.
  • [0054]
    In group three, at 10 minutes after the global ischemia, 0.8-1.2 ml of CSF was withdrawn from caunnulas in cisterna magna and holes of the skull. After the CSF removal, 0.8 ml of the CSF was used to dissolve our composition 1 (64 mg gelatin, 0.72 mg glucose), then was injected back through the caunnulas. The ICP was maintained at 0-70 cm H20.
  • [0055]
    At one hours of the global brain ischemia, the arterial clips were removed and then followed by blood infusion. Phenylephrine (10 mg in 100 ml saline) was given to increase and maintain mean blood pressure between 80-100 mmHg. At 24 hours after ischemic injury, the rabbits were tested for behavioral deficit by the following criteria: Maximum Score=400 (meaning brain death or death); Minimum Score=0 (meaning normal brain)
  • [0056]
    1. Level of consciousness
  • [0057]
    0=complete awareness of auditory stimuli.
  • [0058]
    30=clouded: apparently conscious but drowsy or intermittently irritable on clapping hands and pinching nailbeds of hindlegs.
  • [0059]
    60=stupor: response with movements to pinching nailbed of hindlimb, open eyes, movements may be either purposeful or reflex.
  • [0060]
    100=coma: no movement on painful stimulation (pinching nailbed of hindlimb; should be confirmed on forelimbs as well).
  • [0061]
    2. Respiratory pattern
  • [0062]
    0=normal rate and rhythm.
  • [0063]
    50=abnormal spontaneous breathing (e.g., periodic gasps, irregular rhythm)
  • [0064]
    75=breathing, but not enough to maintain normal arterial blood gases.
  • [0065]
    100=apnea: complete absence of spontaneous respiratory efforts
  • [0066]
    3. Cranial nerve function
  • [0067]
    Pupil size: examine in room lighting and record diameters of pupil and iris (R/L)
  • [0068]
    0=normal: 3-7 mm diameter
  • [0069]
    10=abnormal: greater than 7 mm
  • [0070]
    15=severely abnormal: greater than 10, pinpoint, or new anisocoria
  • [0071]
    Papillary response to light: use flashlight (R/L)
  • [0072]
    0=normal
  • [0073]
    10=sluggish
  • [0074]
    15=absent
  • [0075]
    Eyelid reflex:
  • [0076]
    0=normal
  • [0077]
    10=sluggish
  • [0078]
    15=absent
  • [0079]
    Corneal reflex: Test with moist cotton swab, observe for eyelid closure (R/L)
  • [0080]
    0=normal
  • [0081]
    10=sluggish
  • [0082]
    15=absent
  • [0083]
    Swallow reflex:
  • [0084]
    0=normal:
  • [0085]
    10=absent
  • [0086]
    Auditory-palpebral (startle) reflex: clap hands loudly and observe for motor response
  • [0087]
    0=normal
  • [0088]
    10=no response
  • [0089]
    Gag reflex: stimulate posterior pharynx and observe contraction of the soft palate under direct vision
  • [0090]
    0=normal
  • [0091]
    10=absent
  • [0092]
    Carinal cough reflex: stimulate carina of trachea with suction catheter and observe cough
  • [0093]
    0=normal
  • [0094]
    10=absent
  • [0095]
    4. Motor and sensory function
  • [0096]
    Muscle stretch reflex
  • [0097]
    0=normal in all extremities
  • [0098]
    10=increased or absent 1-3 extremities
  • [0099]
    25=absent in all extremities
  • [0100]
    Motor response to painful stimulus: Pinch each limb, observe for withdrawal response.
  • [0101]
    0=normal 4
  • [0102]
    10=no response
  • [0103]
    25=coma (no test required)
  • [0104]
    Positioning: place rabbit in left lateral decubitus position and observe position assumed.
  • [0105]
    0=normal
  • [0106]
    10=mildly abnormal or intermittent running movements
  • [0107]
    25=markedly abnormal: opistotonus, fixed flexion, total flaccidity, severe running movements
  • [0108]
    Muscle tone: Pick up each extremity and release; observe
  • [0109]
    0=normal
  • [0110]
    10=1 or 2 extremities stiff or flaccid
  • [0111]
    25=3 or 4 extremities stiff or flaccid
  • [0112]
    The results are as follow:
  • [0113]
    In group one, the score is 400. All rabbits died once disconnected from the ventilator.
  • [0114]
    However group two and three treated with composition I and composition II, average scores are about 30-60 (level of consciousness 0-30; respiratory pattern 0; cranial nerve function 0; motor and sensory function 0-30).
  • [0115]
    While my above description contains many specifics, these should not be construed as limitations on the scope of the invention, but rather as illustrative examples.
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US775930921 May 200720 Jul 2010Yanming WangUse of polypeptides in treating tissue injury
US84352049 Oct 20077 May 2013Neurofluidics, Inc.Cerebrospinal fluid purification system
US20060034946 *2 Oct 200416 Feb 2006Yanming WangIrrigating solution for neurosurgical procedures
US20060057065 *11 Sep 200416 Mar 2006Yanming WangComposition and method to prevent and treat brain and spinal cord injuries
US20060057067 *28 Jul 200516 Mar 2006Yanming WangLymph-like composition and method to prevent and treat central nervous system injuries
US20070275896 *21 May 200729 Nov 2007Neuroprotection, Inc.Use of Polypeptides in Treating Tissue Injury
US20090325856 *24 May 200631 Dec 2009GemacComposition Designed For The Treatment Of Multiple Sclerosis
US20100305492 *9 Oct 20072 Dec 2010Shivanand LadCerebrospinal Fluid Purification System
EP2392342A1 *4 Jun 20107 Dec 2011Commissariat Ó l'╔nergie Atomique et aux ╔nergies AlternativesCompositions for use in the treatment or diagnosis of prion diseases
WO2006125930A1 *24 May 200630 Nov 2006GemacComposition for the treatment of multiple sclerosis
WO2011151798A1 *1 Jun 20118 Dec 2011Commissariat A L'energie Atomique Et Aux Energies AlternativesCompositions for use in the treatment or diagnosis of prion diseases
Classifications
U.S. Classification514/8.5, 514/17.2, 514/8.4, 514/19.1, 514/20.1, 514/17.3, 514/15.1, 514/17.4, 514/18.4, 514/14.9, 514/17.7
International ClassificationA61K31/56, A61K31/685, A61K31/355, A61K31/737, A61K31/00, A61K36/48
Cooperative ClassificationA61K31/737, A61K31/685, A61K31/56, A61K31/00, A61K36/48, A61K35/60, A61K31/355
European ClassificationA61K31/00, A61K36/48, A61K31/685, A61K31/56, A61K31/355, A61K31/737, A61K35/60